Single-cell sequencing reveals that endothelial cells, EndMT cells and mural cells contribute to the pathogenesis of cavernous malformations.
Single-cell sequencing reveals that endothelial cells, EndMT cells and mural cells contribute to the pathogenesis of cavernous malformations.
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DOI：
10.1038/s12276-023-00962-w
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发表时间：
2023-03
影响因子：
12.8
通讯作者：
Wang, Yibo
中科院分区：
文献类型：
--
作者：
Ren, Jian;Xiao, Xiao;Li, Ruofei;Lv, Cheng;Zhang, Yu;Wang, Leiming;Hong, Tao;Zhang, Hongqi;Wang, Yibo
侵入中枢神经系统的海绵状血管畸形（CM）发生在约0.16-0.4%的一般人群中，通常导致脑血管畸形和局灶性神经功能缺损。进一步了解疾病机制和治疗策略需要对人类CM有更深入的了解。在此，我们对来自十二个人CM样品和三个对照样品的可存活细胞进行单细胞RNA测序（scRNA-seq）分析。共有112，670个高质量细胞被聚类为11种主要细胞类型，这些细胞类型在携带不同基因突变的CM中具有许多共同特征。一个新的EC亚群标记PLVAP是唯一确定的病变。细胞配体E2受体网络显示，PLVAP阳性EC亚群是所有细胞类型中ANGPT和VEGF信号通路的最强贡献者。PI 3 K/AKT/mTOR通路在PLVAP阳性亚群中被强烈激活，即使在非PIK 3CA突变携带者中也是如此。此外，首次在单细胞水平上在CM中鉴定了内皮-间充质转化（EndMT）细胞，其伴随着强烈的免疫激活。转录因子SPI 1被预测为EndMT的一个新的关键驱动因子，这一点已被体外和体内研究所证实。一种特定的成纤维细胞样表型在病变平滑肌细胞中更为普遍，暗示了CM中血管重建和修复的作用，我们还证实了TWIST 1可以在体外和体内诱导SMC表型转换。我们的研究结果提供了新的见解的病理机制解密和进一步的精确治疗CM。对单细胞中所有RNA的测序为海绵状畸形（CM）的发展提供了线索，CM是大脑或神经系统中薄壁畸形血管的小簇。CM可导致出血或神经系统症状，其原因尚不清楚。由北京协和医学院的Yibo Wang和中国北京首都医科大学的Hongqi Zhang和Tao Hong领导的一个团队对来自CM患者和健康对照样本的10多万个单细胞中的所有RNA进行了测序，使他们能够识别可能导致CM的分子事件。他们证明了基因表达景观是如何改变的，特别是在EC，EndMT细胞和壁细胞中。这些结果为研究CM的遗传和分子原因提供了策略，并可能有助于确定新的治疗方法。
Cavernous malformations (CMs) invading the central nervous system occur in ~0.16–0.4% of the general population, often resulting in hemorrhages and focal neurological deficits. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of CMs in humans. Herein, we performed single-cell RNA sequencing (scRNA-seq) analysis on unselected viable cells from twelve human CM samples and three control samples. A total of 112,670 high-quality cells were clustered into 11 major cell types, which shared a number of common features in CMs harboring different genetic mutations. A new EC subpopulation marked with PLVAP was uniquely identified in lesions. The cellular ligand‒receptor network revealed that the PLVAP-positive EC subcluster was the strongest contributor to the ANGPT and VEGF signaling pathways in all cell types. The PI3K/AKT/mTOR pathway was strongly activated in the PLVAP-positive subcluster even in non-PIK3CA mutation carriers. Moreover, endothelial-to-mesenchymal transition (EndMT) cells were identified for the first time in CMs at the single-cell level, which was accompanied by strong immune activation. The transcription factor SPI1 was predicted to be a novel key driver of EndMT, which was confirmed by in vitro and in vivo studies. A specific fibroblast-like phenotype was more prevalent in lesion smooth muscle cells, hinting at the role of vessel reconstructions and repairs in CMs, and we also confirmed that TWIST1 could induce SMC phenotypic switching in vitro and in vivo. Our results provide novel insights into the pathomechanism decryption and further precise therapy of CMs. Sequencing all the RNA in single cells has provided clues to the development of cavernous malformations (CMs), small clusters of thin-walled misshapen blood vessels in the brain or nervous system. CMs can result in hemorrhage or neurological symptoms, and their causes are poorly understood. A team led by Yibo Wang at Peking Union Medical College and Hongqi Zhang and Tao Hong at Capital Medical University in Beijing, China, sequenced all the RNA in over 100,000 single cells from samples from CM patients and healthy controls, allowing them to identify molecular events that can lead to CMs. They demonstrated how the gene expression landscape is altered, especially in ECs, EndMT cells and mural cells. These results provide a strategy for investigating the genetic and molecular causes of CMs, and may help in identifying new therapies.
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影响因子：
16.6
作者：
Malinyerno, Matteo;Maderna, Claudio;Dejana, Elisabetta
通讯作者：
Dejana, Elisabetta
DOI：
10.1016/j.jcmgh.2015.05.001
发表时间：
2015-07
影响因子：
7.2
作者：
Elkadri A;Thoeni C;Deharvengt SJ;Murchie R;Guo C;Stavropoulos JD;Marshall CR;Wales P;Bandsma R;Cutz E;Roifman CM;Chitayat D;Avitzur Y;Stan RV;Muise AM
通讯作者：
Muise AM
影响因子：
2.6
作者：
Zhang J;Guo JR;Wu XL;Wang X;Zhu ZM;Wang Y;Gu X;Fan Y
通讯作者：
Fan Y
影响因子：
64.8
作者：
Maddaluno, Luigi;Rudini, Noemi;Dejana, Elisabetta
通讯作者：
Dejana, Elisabetta
影响因子：
64.8
作者：
Ben-Zvi, Ayal;Lacoste, Baptiste;Kur, Esther;Andreone, Benjamin J.;Mayshar, Yoav;Yan, Han;Gu, Chenghua
通讯作者：
Gu, Chenghua